This invention relates to the therapeutic treatment of cancers.
In recent years investigators have begun treating cancers with cytokines. The cytokines, which include tumor necrosis factor, interferons, interleukins and various other factors, are a class of immunomodulatory proteins secreted by monocytes, macrophages, and lymphocytes in response to mitogens. Cytokines have demonstrated antiproliferative and cytotoxic effects on some malignant cell lines in vitro, necrosis of tumors in vivo in animal models, and therapeutic effects in some human clinical trials.
Tumor necrosis factor alpha ("TNF.alpha.") has been described as inhibiting the proliferation in vitro of human melanoma cells, primary myeloid cells, and of some but not all myeloid leukemia cell lines when added to the culture media (Helson et al., 1975, Nature, Vol. 258, pp. 731-732; Peetre et al., 1986, Jour. Clin. Invest., Vol. 78, pp. 1694-1700; Munker et al., 1987, Blood, Vol. 69, pp. 1102-1108). Intravenous or intra-tumoral injection of murine TNF.alpha. has also been described as being toxic against both human and murine transplanted tumors in nude mice (Haranaka et al., 1984, Int. Jour. Cancer, Vol. 34, pp. 263-267).
The combination of TNF.alpha. and interferon gamma ("IFN.gamma.") has been demonstrated to be more effective than either cytokine alone in suppressing tumor cell lines in vitro. Addition of TNF.alpha. and IFN.gamma. together to culture media augmented their antiproliferative effects on a subset of murine and human tumor cell lines in vitro (Sugarman et al., 1985, Science, Vol. 230, pp. 943-945). Whereas addition of either TNF.alpha. or IFN.gamma. alone to the culture media of the myeloid leukemia cell line, ML-1, stimulates differentiation, exposure of ML-1 to TNF.alpha. and IFN.gamma. together resulted in cell death (Craig et al., 1989, Jour. Cel. Physiol., Vol. 141, pp. 46-52).
The treatment of transplanted and of chemically induced tumors in mice with TNF.alpha. and IL-2 has been demonstrated to be more effective than the treatment of these tumors with just one of these cytokines (U.S. Pat. No. 4,863,727). Seven dogs that had spontaneous tumors, including melanomas, pharyngeal squamous cell carcinoma, mammary adenocarcinoma, and mast cell tumors, were treated with a combination of TNF.alpha. and IL-2. TNF.alpha. was administered by intravenous injection and IL-2 was administered subcutaneously to each of the seven dogs. Each dog showed some form of response, either in slowed disease progression or reduction of tumor mass.
Clinical trials have also examined the effectiveness of TNF.alpha. and IFN.gamma., administered as an overlapping continuous 24 hour IV infusion, in patients having various sarcomas and carcinomas. Two of 36 patients treated exhibited some response (Demetri et al., 1989, Jour. Clin. Oncol., Vol. 7, pp. 1545-1553).
Clinical trials have shown IFN.gamma. to be effective in treating chronic myelogenous leukemia (U.S. Pat. No. 4,851,219). When used to treat patients who are lodged in teh pre-blastic phase, IFN.gamma. was found to suppress the progression of the disease in 6 of 14 patients.
Leukemia patients have been occasionally observed to undergo "spontaneous remission" when they contract a concurrent acute secondary infection (Pelner et al., 1958, Acta. Med. Scand., Vol. 338 (Suppl), pp. 1-47). The contraction of hepatitis by patients having acute myelogenous leukemia has been observed to prolong survival (Barton et al., 1979, Clin. Res., Vol. 27, pp. 490; Barton et al., 1979, Ann. Int. Med., Vol. 90, pp. 188-190; Foon et al., 1980, JAMA, Vol. 244, pp. 1806-1807; Rotoli et al., 1982, New Eng. Jour. Med., Vol. 307, pp. 1712-1713). The etiology remains unknown.
Bacterial infection can cause toxic shock owing to bacterial lipopolysaccharide endotoxins ("LPS"), and in extreme cases death results. Intravenous injection of endotoxin into normal individuals causes a brief increase of TNF.alpha. levels in plasma (Michie et al., 1988, New. Eng. Jour. Med., Vol. 318, pp. 1481-1486). Additionally, although TNF.alpha. has low toxicity on normal cells when injected subcutaneously into pathogen free mice, it can cause lethal shock and hemorraghic necrosis of tissue when subcutaneously injected into mice concurrently with LPS. In contrast, mice given concurrent subcutaneous injections of IFN.gamma. and LPS or IL-1 and LPS do not exhibit toxic effects (Rothstein et al., 1988, Proc. Natl. Acad. Sci., USA, Vol. 85, pp. 607-611).
Lipopolysaccharide has been described to induce release of TNF.alpha. from monocytes and macrophages in vitro when added to the culture media (Mannel et al., 1980, Infect. Immun., Vol. 30, pp. 523-530) LPS is bound and opsonized by a lipopolysaccharide binding protein ("LBP") (Tobias et al., 1989, Jour. Biol. Chem., Vol. 264, pp. 10867-10871). LBP is present in serum at low levels and is induced during an acute phase response to LPS injected into rabbits. The release of TNF.alpha. by macrophages may be in part mediated by binding of LPS/LBP to the CD14 cell surface receptor (Wright et al., 1990, Science, Vol. 249, pp. 1431-1433). In contrast to monocytes and macrophages, an acute myeloid leukemia cell line, HL60, releases TNF.alpha. in vitro in response to phorbol esters added to the culture media (Aggarwal et al., 1985, Jour. Biol. Chem., Vol. 260, pp. 2345-2354), but not in response to LPS added to the culture media (Mohri et al., 1990, Jour. Immunol., Vol. 144, pp. 2678-2682).